The present invention relates to novel substituted phenyl-piperazine derivatives potently binding to the 5-HT1A receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and/or D3/D4 ligands and are thus considered to be particularly useful for the treatment of depression and psychosis.
Clinical and pharmacological studies have shown that 5-HT1A agonists and partial agonists are useful in the treatment of a range of affective disorders such as generalised anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.
It has also been reported that 5-HT1A ligands may be useful in the treatment of ischaemia.
An overview of 5-HT1A antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al., Serotottin, 1997, Vol. 2, Issue 7. It is stated that 5-HT1A antagonists may be useful in the treatment of schizophrenia, senile dementia, dementia associated with Alzheimer""s disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
5-HT reuptake inhibitors are well known antidepressant drugs and useful for the treatment of panic disorders and social phobia.
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies, it was found that combined 5-HT1A receptor antagonists and scrotonin reuptake inhibitors would produce a more rapid onset of therapeutic action.
Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of neuroleptic drugs, which primarily exert their effect via antagonism of D2 receptors, are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors, and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526 and Sanner Exp. Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620). Furthermore, it has been shown that clozapine, which is an effective antipsychotic, is a silent antagonists (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84).
It has also been suggested that dopamine D4 antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson""s disease with L-dopa (Tahar et al. Eur. J Pharmacol. 2000, 399, 183-186).
Dopamine D3 receptors also belong to the dopamine D2 subfamily of receptors, and they are preferentially located in limbic regions of the brain (Sokoloff et al. Nature, 1990, 347, 146-151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Willner Int. Clinical Psychopharmacology 1997, 12, 297-308). Furthermore, an elevation of the level of D3 receptors in the limbic part of schizophrenic brains has been reported (Gurevich et al. Arch. Gen. Psychiatry 1997, 54, 225-32). Therefore, D3 receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D2 receptors (Shafer et al. Psychopharmacology 1998, 135, 1-16; Schwartz et al. Brain Research Reviews 2000, 31, 277-287).
Moreover, D3 receptor blockade results in a slight stimulation in the prefrontal cortex (Merchant et al. Cerebral Cortex 1996, 6, 561-570), which could be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, dopamine D3 antagonists can reverse D2 antagonist-induced EPS (Millan et al. Eur. J. Pharmacol. 1997, 321, R7-R9) and do not cause changes in prolactin (Reavill et al. J. Pharmacol. Exp. Ther. 2000, 294, 1154-1165). Consequently, D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al. Current Pharmaceutical Design 1997, 3, 391-404).
Accordingly, agents acting on the 5-HT1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity and/or D4 and/or D3 activity may be particularly useful for the treatment of various psychiatric and neurological diseases.
Structural similar compounds to the compounds of the present invention have been described earlier.
Thiophene derivatives are described in WO 9902516 as ligands for the 5-HT1A-receptor.
WO 9726252 describes piperazinyl derivatives as insecticides.
WO 9514004 describes substituted alkylamino-indole derivatives as 5-HT1A, 5-HT1B and 5-HT1D-derivatives.
It has now been found that compounds of a certain class of phenyl-piperazine derivatives bind to the 5-HT1A receptor with high affinities. Furthermore, it has been found that many of these compounds have other highly beneficial properties as i.e. potent serotonin reuptake inhibition activity and/or affinity for the D4 and/or the D3 receptor.
Accordingly, the present invention relates to novel compounds of the general Formula I: 
wherein Z represents NH, NRxe2x80x2xe2x80x3, O or S; Rxe2x80x2xe2x80x3 represents hydrogen, C1-6-alkyl;
R7 and R8 independently represent hydrogen, halogen, C1-6-alkyl, C3-8-cycloalkyl, CN, CF3 or C1-6-alkoxy; or R7 and R8 together form a 5- or 6-membered aryl or heteroaryl fused to the benzene-ring;
Y represents N, C or CH;
the dotted line represents an optional bond;
R6 and R6xe2x80x2 represent H or C1-6-alkyl;
X represents xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94
n is 2, 3, 4 or 5;
m is 2 or 3;
R1, R2, R3, R4 and R5 are independently selected from a group consisting of hydrogen, halogen, C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-8-cycloalkyl, aryl, hydroxy, hydroxy-C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkoxy, C1-6-alkylsulfanyl, acyl, NR9R10 wherein R9 and R10 independently represent hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl or aryl; or R9 and R10 together with the nitrogen to which they are attached form a 1-morpholinyl, 1-piperidinyl, 1-homopiperidinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl, or pyrazolyl, all of which may be further substituted with C1-6-alkyl; or two adjacent substituents of R1-R5 together form a ring fused to the phenyl ring selected from the group consisting of 
wherein W is O or S, and Rxe2x80x2 and Rxe2x80x3 are hydrogen or C1-6-alkyl:
The compounds of the invention have affinity for the 5-HT1A receptor. Accordingly, the invention provides:
A compound as above as a medicament.
A pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
The present invention provides the use of a compound of Formula I as defined above or an acid addition salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
The invention provides a method for the treatment of diseases and disorders in humans caused by abnormalities in the serotonin system of the central nervous system comprising the administration of an effective amount of a compound of Formula I as above.
The compounds of the invention are considered useful for the treatment of affective disorders, such as depression, generalised anxiety disorder, panic disorder, obsessive compulsive disorders, social phobia, and eating disorders, psychosis and neurological disorders such as ischacemia and senile dementia.
A preferred embodiment of the invention is the compound of formula I as above wherein Z is NH and the resulting indole is connected in position 3;
Another preferred embodiment of the invention is the compound of formula I as above wherein R7 and R8 independently are selected from a hydrogen, halogen, C1-6-alkyl or R7 and R8 together form a fused pyridyl-ring;
Another preferred embodiment of the invention is the compound of formula I as above wherein n is 2, 3 or 4;
Another preferred embodiment of the invention is the compound of formula I as above wherein m is 2;
Another preferred embodiment of the invention is the compound of formula I as above wherein R6 and R6xe2x80x2 are both hydrogen;
Another preferred embodiment of the invention is the compound of formula I as above wherein Y is N;
Another preferred embodiment of the invention is the compound of formula I as above wherein R1, R2, R3, R4 and R5 are independently selected from hydrogen, alkoxy, NR3R4 wherein R3 and R4 independently represent hydrogen, C1-6-alkyl; or R3 and R4 together form a 1-morpholino; or two of adjacent of R1, R2, R3, R4 and R5 together form a fused ring consisting of
xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, or
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94;
Another preferred embodiment of the invention is the compound of formula I as above wherein one or two of R1, R2, R3, R4, R5 are not hydrogen;
The most preferred embodiment of the invention is the compound according to formula I as above, the compound being:
1-{1-[3-(dimethylamino)phenoxy]phenyl}-4-[2-(1H-indol-3-yl)ethyl]piperazine;
1-[1-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[2-(1H-indol-3-yl)ethyl]piperazine;
1-{1-[3-(dimethylamino)phenoxylphenyl}-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-[1-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(6-chloro-1H-indol-3-yl)propyl]piperazine,
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine,
1-[2-(1,4-Benzodioxan-6-yloxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine
1-[2-(1,4-Benzodioxan-5-yloxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine
1-[2-(1,4-Benzodioxan-5-yloxy)phenyl]-4-[3-(6-chloro-1H-indol-3-yl)propyl]piperazine
1-[2-(1,4-Benzodioxan-6-yloxy)phenyl]4-[3-(6-chloro-1H-indol-3-yl)propyl]piperazine
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(6-chloro-1H-indol-3-yl)propyl]piperazine
1-[2-(3-Methoxyphenoxy)phenyl]-4-[3-(6-chloro-1H-indol-3-yl)propyl]piperazine
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[4-(1H-indol-3-yl)butyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[4-(1H-indol-3-yl)butyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine;
1-[2-(3-(Dimethylamino)phenoxy)phenyl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[4-(1H-indol-3-yl)butyl]piperazine;
1-[2-(4-Methoxyphenoxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-[2-(3-(Dimethylamino)phenoxy)phenyl]-4-[4-(1H-indol-3-yl)butyl]piperazine;
1-(2-Phenoxyphenyl)-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine;
1-[2-(1,4-Benzodioxan-5-yloxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
1-[2-(2,6-Dimethoxyphenoxy)phenyl]-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-(Dimethylamino)phenoxy)phenyl]-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(7-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(5-iodo-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(7-chloro-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5,7-difluoro-1H-indol-3-yl)propyl]piperazine
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(7-bromo-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-(Dimethylamino)phenoxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5-iodo-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(2,6-Dimethoxyphenoxy)phenyl]-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(1H-pyrrolo[3,2-h]quinolin-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(5,7-difluoro-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5-iodo-1H-indol-3-yl)propyl]piperazine;
1-[2-(2-Methoxyphenoxy)phenyl]-4-[3-(1H-pyrrolo[3,2-h]quinolin-3-yl)propyl]piperazine;
1-[2-(3-Methoxyphenoxy)phenyl]-4-[3-(1H-pyrrolo[3,2-h]quinolin-3-yl)propyl]piperazine;
1-[2-(1,4-Benzodioxan-5-yloxy)phenyl]-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(2,6-Dimethoxyphenoxy)phenyl]-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-Methoxyphenoxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-[2-(1,4-Benzodioxan-5-yloxy)phenyl]-4-[3-(1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
1-{2-[3-(Morpholin-4-yl)phenoxy]phenyl}-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-Methoxyphenoxy)phenyl]-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-Ethoxyphenoxy)phenyl]-4-[3-(5-methyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(2,6-Dimethoxyphenoxy)phenyl]-4-[3-(5-iodo-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-(Diethylamino)phenoxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-[2-(2,6-Dimethoxyphenoxy)phenyl]-4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazine;
1-{2-[3-(Morpholin-4-yl)phenoxy]pbenyl}-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
1-{2-[3-(Morpholin-4-yl)phenoxy]phenyl}-4-[3-(5-chloro-1H-indol-3-yl)propyl]piperazine;
1-{2-[3-(Morpholin-4-yl)phenoxy]phenyl}-4-[3-(5-iodo-1H-indol-3-yl)propyl]piperazine;
1-[2-(3-Methoxyphenoxy)phenyl]-4-[3-(7-fluoro-1H-indol-3-yl)propyl]piperazine;
1-(2-Phenoxyphenyl)-4-[3-(5,7-dimethyl-1H-indol-3-yl)propyl]piperazine;
1-[2-(1,3-Benzodioxolan-5-yloxy)phenyl]-4-[3-(7-bromo-1H-indol-3-yl)propyl]piperazine;
1-[2-(3,4,5-Trimethoxyphenoxy)phenyl]-4-[3-(5-bromo-1H-indol-3-yl)propyl]piperazine;
Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, inclusive and the groups are having at least one double bond or triple bond respectively;
Halogen means fluoro, chloro, bromo, or iodo.
The term C3-8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferred embodiments are cyclopropyl, cyclopentyl, cyclohexyl.
The terms C1-6 alkoxy, C1-6 alkylsulfanyl, C3-8-cycloalkoxy, designate such groups in which the alkyl group is C1-6 alkyl as defined above.
Acyl means CHO and xe2x80x94CO-alkyl wherein the alkyl group is C1-6 alkyl as defined above.
5- or 6-membered rings which are aryl or heteroaryl designates groups such as phenyl, pyrrolyl, pyridyl, pyrimidyl, furanyl, thienyl;
Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or 1- (tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
The compounds of the invention can be prepared by one of the following methods comprising:
a) reacting a secondary amine of the formula 
wherein R1-R6xe2x80x2, X, Y and m are as defined above with an alkylating agent of the general formula: 
and R7, R8, Z and n are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate;
b) reacting a compound of the formula 
wherein R1-R6xe2x80x2, X, Y, n and m are as defined above and Q(OH)2 is a diol such as substituted ethylene glycol or propylene glycol or a polymer bound diol;
with a hydrazine of the formula 
c) reducing an amide of formula 
wherein Z, R1-R8, X, Y, n and in are as defined above.
d) reducing a compound of formula 
wherein R1-R8, Y, X and in are as defined above
The alkylations according to method a are generally performed by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as acetone, acetonitrile, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone in the presence of a base such as triethylamine or potassium carbonate and optionally a catalytic amount of potassium iodide.
1) 
Secondary amines of formula III are prepared by the reaction sequence outlined above. 2-Fluoro-nitrobenzene is reacted with a nucleophile of formula VIII in an aprotic solvent such as N,N-dimethylformamide using organic or inorganic basis at elevated temperature. After reduction of the intermediate nitro compound IX using standard conditions such as palladium catalysed hydrogenation or iron in acidic solvents, the aniline derivative X was transformed into the desired secondary amine of formula III. The piperazine formation was either performed by reaction with bis(2-chloroethyl)amine, hydrochloride at elevated temperature or in a multistep synthesis according to published procedures (Kruse et al., Recl. Trav. Chim. Pays-Bas, 1988, 107, 303-309).
2) 
Alternatively, secondary amines of formula III are prepared using the mono substituted cyclic diamines of formula XII as key intermediate. The substituent R is an appropriate protecting group such as a ethoxy-, methoxy- or 2-methyl-2-propyloxy-carbonyl group or a benzyl group, or a suitable solid support such as a Merrifield resin or a solid supported carbamate group such as the wang resin based carbamate linker (Zaragoza, Tetrahedron Lett., 1995, 36, 8677-8678). The mono substituted cyclic diamines of formula XII are prepared from commercially available starting materials or by methods obvious to the chemist skilled in the art. The mono substituted cyclic diamine of formula XII are reacted with xcex76-1,2-dichlorobezene-xcex75-cyclopentadienyliron(II) hexafluorophosphate at elevated temperature in an aprotic solvent such as dry tetrahydrofuran using an appropriate base such as potassium carbonate. xcex76-1,2-dichlorobezene-xcex75-cyclopentadienyliron(II) hexafluorophosphate are prepared in analogy to literature procedures (Pearson and Gelormani, J. Org. Chem. 1994, 59, 4561-4570). The thus formed mono chloro derivative of formula XIII are subsequently reacted with a nucleophile of formula VIII in an aprotic solvent such as dry tetrahydrofuran either by the use of an appropriate base such as potassium carbonate or by deprotonation of the nucleophile of formula VIII using a base such as sodium hydride prior to the reaction. Decomplexation, performed according to literature procedures (Pearson et al., J. Org. Chem. 1996, 61, 1297-1305), followed by deprotection by methods obvious to the chemist skilled in the art or cleavage from the solid support according to literature procedures (Zaragoza, Tetrahedron Lett., 1995, 36, 8677-8678 and Conti et al., Tetrahedron Lett., 1997, 38, 2915-2918) afforded the desired secondary amines of formula III, corresponding to secondary amines of formula XV, R. H. Nucleophiles of formula VIII are commercially available, prepared by methods obvious to the chemist skilled in the art or according to literature procedures (Guillaumet and Hretani, J. Heterocyclic Chem., 26, 193-196, 1989).
The alkylating agents of formula 
are prepared according literature procedures (J. Med. Chem. 1983, 26, 1470-1477, Brodfuehrer et al., J. Org. Chem. 1997, 62, 9192-9202, Anelli, et al., J. Org. Chem. 1987, 52, 2559-2562, Brodfuehrer, et al., J. Org. Chem. 1997, 62, 9192-9202) or by methods obvious to the chemist skilled in the art.
The indole formation according to method b is performed by the reaction of acetals of formula IV with aryl hydrazines of formula V resulting in the corresponding hydrazones, which subsequently are converted into indoles by means of the Fischer indole synthesis. The synthesis sequence is preferably performed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron trifluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature.
Acetals of formula IV are prepared by the reaction sequence 2) outlined above using mono substituted cyclic diamines of formula XII wherein 
as key intermediates. The key intermediates of formula XII are prepared by alkylation of cyclic diamines of formula XI with acetals of formula 
using the conditions described above for methods a.
Polymer bound acetals of formula XVI are prepared by reaction of aldehydes of formula Gxe2x80x94(CH2)n+1xe2x80x94CHO with commercially available 2,2-dimethyl-1,3-dioxolan-4-yl-methoxymethyl polystyrene in a suitable solvent such as toluene, using p-toluenesulfonic acid as catalyst at elevated temperature. 4-Chlorobutanal, 5-chloropentanal, and 6-chlorohexanal were prepared in analogy to the method described by Normant et al., Tetrahedron 1994, 50 (40), 11665.
The reductions according to Method c and d are generally performed by use of LiAlR4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature. The amides of formula VI are prepared from secondary amines of formula III and a substituted indol-3-ylalkylcarboxylic acids or carboxylic acid chlorides by methods obvious to the chemist skilled in the art. The amides of formula VII are prepared from 3-unsubstituted indoles and secondary amines of formula III according to literature multistep procedures (Nichols al., Synthesis 1999, 6, 935-938 and Speeter and Anthony, J. Am. Chem. Soc. 1954, 76, 6208-6210)